Adenosine is a product of ATP hydrolysis released from hypoxic tissues. This nucleoside attenuates the response to catecholamines, and regulates blood flow to many organs during ischemia. Adenosine and its receptor blocker caffeine, also influence the decline in blood pressure (BP) that occurs with hemorrhage. The broad, long-term objectives of this research are to determine whether endogenous adenosine causes or contributes to the hypotension that occurs with hemorrhage, whether it modifies the response to treatments for hypotension, and whether adenosine-mediated neurotransmission influences survival. Specific Aims examine adenosine's influence on BP at varying levels of blood loss; its effects on the hemodynamic responses to the administration of blood or saline solutions; the effects of peripheral or central adenosine receptor blockade on hemodynamics during hemorrhagic shock; the adenosine receptor subtype(s) most likely involved in the response to hemorrhage (including whether selective adenosine receptor blockade accentuates ischemia in specific organs); and whether adenosine or adenosine receptors influence the sensitivity to vasopressors. Experiments use intact animal models of hemorrhagic shock, in contrast to most studies, which have been performed in vitro. Adenosine-mediated neurotransmission will be examined 1) by measuring plasma adenosine during hemorrhage; 2) by examining changes in BP and HR in animals subjected to caffeine or 8 sulfophenyltheophylline pretreatment, caffeine withdrawal, selective blockade of A1 or A2 adenosine receptors, or of receptors located in the central nervous system or in the periphery, and 3) by examining the effects of endogenous adenosine on the response to phenylephrine. This work is health-related in that adenosine may alter survival by contributing to the pathophysiology of hypotension, and that it may also attenuate the response to compensatory mechanisms and therapeutic modalities during hemorrhage. Potential benefits of methylxanthines and their synthetic derivatives, or hazards of caffeine withdrawal may also be identified.